毒理学相关资料,第八章内容参考文献7.pdfVIP

Int. J. Cancer: 83, 151–156 (1999) Publication of the International Union Against Cancer Publication de l’Union Internationale Contre le Cancer 1999 Wiley-Liss, Inc. MOLECULAR EFFECTS OF PACLITAXEL: MYTHS AND REALITY (A CRITICAL REVIEW) Mikhail V. BLAGOSKLONNY* and Tito FOJO Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA Recent studies on paclitaxel (Taxol), a microtubule- nanomolar or less (Huizing et al., 1993). Therefore, activity which stabilizing agent and effective anti-cancer drug, have identi- requires paclitaxel doses as high as 10 to 30µM may not be fied numerous cellular and molecular effects, such as induc- clinically significant. Furthermore, since paclitaxel accumulates in tion of cytokines and tumor-suppressor genes, indirect cytotoxicity due to secretion of tumor necrosis factor, vast cultured monolayer cells in vitro at concentrations substantially activation of signal-transduction pathways and selective activ- higher than those in culture medium (Jordan et al., 1996), much ity against cells lacking functional p53. Some of these results, higher concentrations must be achieved in blood to parallel the in including the immediate activation of signaling pathways and vitro conditions. As an example, multicellular spheroids, an in vitro gene expression, have been observed only with paclitaxel model thought to more closely mimic solid tumors, have been concentrations 1,000-fold higher than those required for shown to be 100-fold less sensitive to paclitaxel than cells